Autoimmune diseases are any diseases caused by immune cells that become misdirected toward healthy cells and/or tissues of the body, generally due to a breakdown of the body's mechanisms assuring the recognition of self from non-self. Autoimmune diseases are classified into two basic categories: antibody-mediated diseases such as systemic lupus erythematosus (SLE), pemphigus vulgaris, myasthenia gravis, hemolytic anemia, thrombocytopenia purpura, Grave's disease, Sjogren's disease and dermatomyositis; and cell-mediated diseases such as Hashimoto's disease, polymyositis, inflammatory bowel disease, multiple sclerosis (MS), diabetes mellitus, rheumatoid arthritis (RA), and scleroderma.
Apoptosis is an important mechanism in immune system regulation, responsible for elimination of autoreactive T-lymphocytes (T cells), B-lymphocytes (B cells) and monocytes from the circulation and prevention of their entry into the central nervous system (CNS). Recent studies have implicated apoptotic cell death pathways in initiating and propagating autoimmune diseases, as well as rendering individuals susceptible to such diseases (Mahoney and Rosen, Current Opinion in Immunology, 17:583-588, 2005). There is substantial evidence suggesting that autoreactive T cells which have deficiencies in their ability to undergo programmed cell death (i.e., failed apoptosis) are a primary culprit in many autoimmune disorders, including MS, RA and SLE. Id.
Interferon is an important cytokine which has multiple effects on the immune response (Theofilopoulos et al., Annu. Rev. Immunol., 23:307-336, 2005). Interferons include type 1 interferons (e.g., interferon-alpha (IFN-α) and interferon-beta (IFN-β)) and type 2 interferons (e.g., interferon-gamma (IFN-γ)). All type 1 IFNs are recognized by a shared receptor (IFN-αR) composed of two transmembrane proteins, IFN-αR1 and IFN-αR2. Immunomodulatory therapy with IFN-β has proven to be successful in reducing the severity of the underlying disease in patients with relapsing-remitting MS. FDA-approved IFN-β therapies for the treatment of relapsing-remitting MS in the United States include interferon β-1a (marketed as Avonex®, available from Biogen, Inc.), interferon-β-1b (marketed as Betaseron®, available from Chiron Corporation) and interferon β-1a (marketed as Rebif®, available from EMD Serono and Pfizer), having combined sales exceeding three billion dollars a year. Unfortunately, each of these therapeutic agents are only partially effective in reducing the frequency and severity of relapses, slowing the rate of disease progression, or reducing the degree of brain inflammation as measured by a variety of magnetic resonance imaging (MRI) techniques. There is a continuous need for more effective IFN-β products, as well as more efficient methods of making them.
Provided herein are the next generation of safer and more effective treatments for autoimmune diseases using genetically engineered fusion molecules comprising one or more IFN molecules attached to an antibody which has been specifically selected based on its ability to bind to a antigen determined to be a specific target antigen, and wherein the specific target antigen is determined to be differentially expressed or up-regulated on activated T cells as compared to resting T cells. Importantly, the engineered antibody-interferon fusion molecules of the present invention retain the potent cytotoxic effects of the IFN at optimum concentrations and with reduced systemic toxicities, thus improving the ability of the antibody-interferon fusion molecules to kill activated T cells and/or impair the functions of activated T cells, and thus providing for monoclonal antibody/IFN-based therapies having superior efficacy and safety profile for the treatment of autoimmune diseases.